This invention relates to the treatment of cervical or vaginal neoplasia including cervical intraepithelial neoplasia (xe2x80x9cCINxe2x80x9d), intraepithelial neoplasia, vulvar intraepithelial neoplasia and ano-genital warts, and in particular, provides a method of treatment to prevent these conditions from progressing into cancer. Treatment in accordance with the present invention utilizes an effective amount of indole-3-carbinol (xe2x80x9cI3Cxe2x80x9d) and/or diindolylmethane (xe2x80x9cDIMxe2x80x9d).
Human papillomavirus (xe2x80x9cHPVxe2x80x9d) infection of the lower genital tract is the most common sexually transmitted viral disease in the United States. (Husseinzadeh, N., et al., xe2x80x9cSubclinical Cervicovaginal Human Papillomavirus Infections Associated with Cervical Condylomata and Dysplasia Treatment Outcomes,xe2x80x9d J. Reprod. Med., Vol. 39, 777-80, (1994)). Most of these viral infections remain dormant and never result in clinically evident disease. However, in some cases, the virus may propagate and cause clinically recognizable HPV-associated changes, including condylomata (genital warts), precancerous lesions of the cervix, as well as invasive cervical cancer. Cancer of the cervix is the second most common cancer in women and the seventh most common form of cancer worldwide. (World Health Organization, xe2x80x9cThe World Health Report,xe2x80x9d Geneva: WHO, (1997)). The association between HPV infection and genital cancer is well documented. (Richart, R., xe2x80x9cCauses and Management of Cervical Intraepithelial Neoplasia,xe2x80x9d Vol. 60, Cancer, 1951-1959, (1987); Schiffman, M. et al., xe2x80x9cEpidemiologic Evidence Showing that Human Papillomavirus Infection Causes Most Cervical Intraepithelial Neoplasia,xe2x80x9d Vol. 85, J. Nat""l Cancer Inst., 958-964, (1993)).
Not all dysplastic lesions develop into cancer. Mildly dysplastic lesions will spontaneously regress without therapy in the majority of patients, and only a small subset of cases actually possess cancerous potential. Less than one half of more severely dysplastic lesions in patients will eventually progress to invasive disease. (Barron, B. and Richart, R., xe2x80x9cStatistical Model of the Natural History of Cervical Carcinoma. II. Estimates of the Transition Time from Dysplasia to Carcinoma In Situ,xe2x80x9d Vol. 45, J. Nat""l Cancer Inst., 1025, (1970)). The progression of HPV infection to genital cancer is therefore not absolute, and other factors (e.g., smoking, diet, and immunosuppression) probably contribute to the progression.
There is currently no available test that can accurately predict the clinical behavior of a cervical lesion. Therefore, most high-grade lesions are treated with surgical excision or ablative therapy. Chemoprevention is the attempt to use natural and synthetic compounds to intervene in the early precancerous stages of carcinogenesis, before invasive disease begins. There is currently no chemopreventative therapy that prevents or impedes the progression of CIN, intraepithelial neoplasia, vulvar intraepithelial neoplasia and ano-genital warts to cancer.
Many families of fruits and vegetables contain relatively high concentrations of unique phytochemicals with potential cancer-preventing properties. As a general matter, diets high in cruciferous vegetables (e.g., broccoli, cabbage, cauliflower, bok-choi, and brussels sprouts) can retard cancer growth in animals and increased consumption of these vegetables by humans has been associated with decreased cancers of the colon, lung, and breast. (Wattenberg, L. W. and Loub, W. D., xe2x80x9cInhibition of Polycyclic Aromatic Hydrocarbon-Induced Neoplasia by Naturally Occurring Indoles,xe2x80x9d Vol. 38, Cancer Res., 1410-1413, (1978)). The specific method of action, however, has not been identified. It has been observed that a specific compound found in crucifers, indole-3-carbinol (xe2x80x9cI3Cxe2x80x9d), may be able to prevent or halt carcinogenesis in certain cases. (Grubbs C. J. et al., xe2x80x9cChemoprevention of Chemically-Induced Mammary Carcinogenesis by Indole-3-Carbinol,xe2x80x9d Vol. 15, Anticancer Res., 709-716, (1995)). Grubbs et al. showed that I3C was effective in inhibiting mammary carcinogenesis in a rat model. Newfield et al. showed that I3C inhibits growth of HPV-induced benign tumors of laryngeal tissue in a mouse model. (Newfield et al., xe2x80x9cEstrogen Metabolism and Human Papillmavirus-Induced Tumors of the Larynx: Chemo-Prophylaxis with Indole-3-Carbinol,xe2x80x9d Vol. 13, Anticancer Res., 337-341, (1993)). Although Newfield et al. suggested the possibility that a diet high in cruciferous vegetables or the consumption of an I3C supplement could perhaps be used to prevent human papillomavirus-induced tumors of the larynx or genital tract, no evidence was presented that I3C would effectively treat CIN in either mice or humans. (Newfield et al., at 340). It is well known that work in animals on one form of cancer is not predictive of the efficacy of that agent to impede or cure cancer of another form in humans.
Similarly, I3C has been used as a dietary supplement for humans to aid in the inhibition of laryngeal papillomatosis. (Coll, D. et al., xe2x80x9cTreatment of Recurrent Respiratory Papillomatosis with Indole-3-Carbinol,xe2x80x9d Vol. 18, Am. J. Otolaryngol., 283-285, (1997)). However, Coll provides no evidence that I3C would treat CIN or other forms of cervical or vaginal neoplasia in humans.
We have discovered that treatment of humans using a therapeutic amount of I3C is effective in the treatment of cervical intraepithelial neoplasia (xe2x80x9cCINxe2x80x9d), independent of HPV infection. Roughly half of the patients with CIN experienced complete regression of the CIN after 12 weeks of daily oral administration of I3C. The use of I3C and/or DIM can be used to cause regression or to prevent the progression to cancer of other forms of cervical or vaginal neoplasia including intraepithelial neoplasia, vulvar intraepithelial neoplasia and ano-genital warts